Project Summary/Abstract The overall goal of the proposed studies is disruption in sympathetic nervous system (SNS) tone during epileptogenesis that contributes to cardiac alterations and potentially sudden death and test whether the cardiac phenotype can be rescued with central modulation of SNS signaling. In sudden unexpected death in epilepsy (SUDEP) affecting humans, the underlying mechanisms are not fully understood but include cardiac and respiratory dysfunction/failure. The focus of this proposal is on cardiac alterations and the role of abnormal SNS tone underlying these phenotype changes in a mouse model of acquired epilepsy with altered SNS tone, cardiac changes, and SUDEP. Detrimental cardiac effects following experimental SE that persist during the development of epilepsy have been shown. Furthermore, pretreatment with a systemic ?1-adrenergic receptor antagonist, blocked some acute changes following SE and stimulation-induced arrhythmias in chronic epilepsy, supporting increased SNS drive in SE and epilepsy. Alterations in SNS drive have not been fully characterized in epileptogenesis, and whether modulation of SNS tone is protective against chronic cardiac changes in epilepsy and associated sudden death has not been evaluated. Mechanisms underlying increased SNS tone following SE are unclear. SNS activity is regulated at many levels in the central nervous system (CNS) with final convergence at the rostral medulla (RM) neurons, which are critical modulators of SNS tone. Models of sympathoexcitation exhibit elevated angiotensin II (ANG II) levels in the RM, which binds to angiotensin type 1 (AT1) and type 2 (AT2) receptors. Activation of excitatory AT1 receptors in the RM is implicated in the maintaining elevated SNS tone, while AT2 receptor activation has an inhibitory effect. In sympathoexcitatory models with similar cardiac alterations as seen post-SE, in RM there are increased AT1 and decreased AT2 receptos. Increased ANG II levels in the brainstem with increased SNS tone has been shown in epilepsy. We hypothesize that persistently increased SNS tone contributes to cardiac dysfunction following SE with altered ANG II signaling as a candidate mechanism. We propose that alterations in ANG II signaling following SE are centrally driven. The aims of the proposed studies will test this hypothesis.